This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mutational activation of EGFR kinase is an important cause of human non-small cell lung cancer (NSCLC). Small molecule drugs, Iressa and Tarceva, are effective in treating the disease caused by some types of the EGFR mutations, but the duration of efficacy is limited due to the emergence of a new mutation T790M in the EGFR kinase that confers resistance to the current drugs. We have identified several new compounds that can specifically inhibit EGFR kinase bearing the T790M mutation. There is a good chance that these new compounds can be used to treat the drug-resistant NSCLC after optimization. In this subproject we aim to solve the drugresistant EGFR mutant kinase in complex with these new compounds. This study will form the basis for optimization of these compounds.